Squamous cell carcinoma of the head and neck (H&N) is a common and debilitating malignancy. Available therapies lead to unsatisfactory survival and are associated with excessive toxicity. The goal of this Project is to define more consistently curative and less toxic therapies. The Project will evaluate whether the tumor vasculature and/or tumor cells are targets when investigating Ad.Egr-TNF.11D (TNFerade, GenVec) given together with standard radiotherapy (XRT) or chemoradiotherapy (CT/XRT). Ad.Egr-TNF.11D is an E1, E2, E3 deleted adenoviral vector that encodes a radio-inducible promoter upstream from a cDNA for human TNF-alpha, a cytokine that has potent antitumor and radiation sensitizing effects, mediated via vascular necrosis and thrombosis. We will investigate whether STAT1, a principal upstream component of the interferon signaling pathway is a predictor of resistance to Ad.Egr-TNF.11D/XRT or CT and represents a potential future target for additional XRT modulation research. Aim 1A will investigate whether the addition of Ad.Egr-TNF.11D to standard XRT is safe and active when given to poor-risk patients with advanced H&N cancer in a clinical phase I/I I trial. Aim 1B will investigate the administration of the agent with CT/XRT in patients with regionally recurrent previously irradiated H&N cancer. Aim 1C will evaluate local induction of TNF-alpha protein within the tumor microenvironment following injection of Ad.Egr-TNF.11D and XRT in biopsy specimens collected prior to and during therapy. Aim 2 will focus directly on the tumor cells. Here we will further explore previous observations suggesting that STAT 1 overexpression is associated with intrinsic tumor cell resistance. Aim 3 will focus on correlative imaging studies in animal tumor models. MRI measurements will be performed to detect changes in blood flow and/or vascular destruction and cell death following treatment with ad.Egr-TNF.11D and XRT. These studies will lead to new therapies and future clinical trials.